Osteoporosis Resources for Primary Care: Investigation

National vitamin D guidelines

Guidelines on vitamin D supplementation have been published by the ROS. These have been endorsed by the Royal College of Nursing, Bone Research Society, British Dietetic Association, Paget's Association, International Osteoporosis Foundation, UK Clinical Pharmacology Association, Primary Care Rheumatology Society, Royal Pharmaceutical Society, British Orthopaedic Association and the Society for Endocrinology.

These guidelines do not address supplementation in pregnant women, although this is covered in NICE guidance.

Guidelines to ensure adequate vitamin D levels are important because in the UK we become vitamin D deficient every year between October and April. Many high-risk frail people are also housebound throughout the year. People who have had a previous skin cancer will have been advised not to sunbathe, and others may be on medications (such as amiodarone) that are a contraindication to sunbathing.

Rickets, a disease associated with Victorian times, is now returning, so efforts to combat the condition are needed. Furthermore, vitamin D repletion is important to ensure efficacy of bone-strengthening treatments in our ageing population, as is calcium repletion.

Most elderly patients have dietary deficiency of calcium either because they are trying to cut down their cholesterol, or are too poor to eat properly. The housebound/residential care home patients rarely get out, even when the sun occasionally shines. For drugs like denosumab and zoledronate it is often part of agreed protocols that the vitamin D level has to be > 50 nmol/L to give the drug. Simply by correcting vitamin D deficiency you can make people feel better, sometimes relieve myalgia (especially in patients on aromatase inhibitors), and improve muscle strength reducing risk of falls and fracture, as well as ensuring the efficacy of the active treatment.

The British National Formulary (BNF) now lists a variety of vitamin D formulations, alone or in combination with calcium. Many people don't like taking calcium + vitamin D tablets because they are too gritty, 'taste like chalk', 'are too sweet', or give constipation and/or headaches. Some patients stop taking calcium + vitamin D supplements due to fears about side effects including cardiovasular problems. Some research studies have suggested patients may have an increased risk of heart attack if they take high doses of a calcium supplement alone or calcium and vitamin D together although the incidence of heart attack is still low. The conclusions of other research, however, has found that taking calcium and vitamin D supplements does not increase risk of heart attack or stroke. The UK Medicines and Healthcare products Regulatory Agency (MHRA) looked at the research findings and recommended that doctors still need to ensure patients are getting sufficient calcium especially if they are taking osteoporosis drug treatment. For more information for you and your patients, download the ROS 'Calcium supplements and blood tests' factsheet.

There are some new high-dose vitamin D products (cholecalciferol or vitamin D3) listed in the BNF so that GPs can prescribe vitamin D3 alone on an FP10, to correct vitamin D deficiency (InVita D3 50,000 IU once a week for 6-8 weeks and re-check, or the 3,200 IU Fultium once daily for 6 – 8 weeks and re-check) or a maintenance dose (Fultium 800 IU once daily, or Invita D3 1400 – 2000 IU once a day). The advantage of this for our frail elderly population is the medication can go in the Nomad, so improving adherence, rather than an over-the-counter preparation which may be forgotten about.

It should be noted that Fultium D3 capsules were re-formulated in October 2014. The old formulation of 800 IU and 3200 IU capsules contained arachis oil so were not suitable for people with a peanut or soya allergy. The new formulations and the 20,000 IU capsules now contain maize oil instead. In case old formulations containing arachis oil are still available it would be important that the pack is checked before dispensing to a patient with a known peanut or soya allergy. InVita D3 contains olive oil.

It should also be noted that the vitamin D in both preparations is made from irradiation of lanolin from sheep's wool so may be unacceptable to vegans. Additionally, the gelatin capsule formulations of both preparations are made from animal products so would not be suitable for either vegetarians or vegans.

Vitamin D is essential for musculoskeletal health. It is required for optimal mineral metabolism and the control of calcium and phosphate homeostasis, it promotes calcium absorption from the bowel, enables mineralisation of newly formed osteoid tissue in bone and plays an important role in muscle function. Rickets in children and osteomalacia in adults are the main manifestations of vitamin D deficiency. Less severe vitamin D deficiency may lead to secondary hyperparathyroidism, bone loss, muscle weakness, falls and fragility fractures in older people.

Vitamin D testing should be prioritised to those patients where the outcome will alter clinical management:

1. Patients with bone diseases that may be improved with vitamin D treatment
   
   Correcting vitamin D deficiency is essential for patients with osteomalacia and is beneficial for patients with osteoporosis. This does not mean that patients with osteoporosis should undergo routine vitamin D testing. Calcium and vitamin D3 supplementation is common practice in those on treatment for osteoporosis, and testing vitamin D levels in patients where the decision has been made to co-prescribe is unlikely to change patient management.
   
   
2. Patients with bone diseases, prior to specific treatment where correcting vitamin D deficiency is appropriate
   
   Ensuring patients receiving potent anti-resorptive osteoporosis treatments (denosumab or zoledronate) are not vitamin D deficient before starting treatment is required to avoid the development of hypocalcaemia.
   
   
3. Patients with musculoskeletal symptoms that could be attributed to vitamin D deficiency

Symptoms of vitamin D deficiency are unfortunately vague and it can be difficult to ascertain whether a low serum 25-hydroxy vitamin D (25OHD) level is causal or a surrogate marker (e.g. of poor nutrition or a lack of outdoor activity). Nonetheless, if patients are suspected of having symptoms caused by osteomalacia, or have chronic widespread pain, a case can be made to measure vitamin D as part of their clinical and laboratory evaluation.

NICE Public Health Guideline. Vitamin D: Supplement Use in Specific Population Groups [PH56]

These guidelines were updated in May 2017 after publication of The SACN vitamin D and health report 2016 and cover vitamin D supplementation in the context of the general population. The guidance includes the following groups of people as being at-risk of vitamin D deficiency:

• All pregnant and breastfeeding women, particularly teenagers and young women
• Children under 3 years
• People over 65 years
• People who have low or no exposure to the sun. For example, those who cover their skin for cultural reasons, who are housebound or confined indoor for long periods
• People who have darker skin, for example, people of African, African-Caribbean and South Asian origin

NICE directs primary care practitioners to look specifically at Recommendation 8 of the guidance which is to ensure health professionals recommend vitamin D supplements. This includes recording vitamin D supplement use among at-risk groups whenever possible.

The recommended definition of deficiency made for adopting into UK practice is:

• Serum 25OHD <25 nmol/L is considered to be vitamin D deficient
• Serum 25OHD of 30 – 50 nmol/L may be inadequate in some people
• Serum 25OHD > 50 nmol/L is sufficient for almost the whole population

Following measurement of serum 25OHD, consider:

• Fragility fracture, documented osteoporosis or high fracture risk
• Treatment with anti-resorptive medication for bone disease
• Symptoms suggestive of vitamin D deficiency
• Increased risk of developing vitamin D deficiency in the future because of reduced exposure to sunlight, religious dress code, dark skin, etc
• Raised parathyroid hormone levels
• Medication with anti-epileptic drugs or oral glucocorticoids
• Conditions associated with malabsorption

In patients whose tests show they have sufficient vitamin D levels (> 50 nmol/L) the recommendations are to give lifestyle advice on maintaining adequate vitamin D levels through safe sunlight exposure and diet. For more information, see the Initiation section of this resource.

The key aims of treatment are:

• Using adequate doses to ensure correction of vitamin D deficiency (to > 50 nmol/L)
• Timely reversal of the clinical consequences of vitamin D deficiency
• Avoiding toxicity

Oral vitamin D3 is recommended as the treatment of choice in vitamin D deficiency.

Where rapid correction of vitamin D deficiency is required, such as in patients with symptomatic disease or about to start treatment with a potent antiresorptive agent (zoledronate or denosumab), the recommended treatment regimen is based on fixed loading doses followed by regular maintenance therapy:

• a loading regimen to provide a total of approximately 300,000 IU vitamin D, given either as separate weekly or daily doses over 6 to 10 weeks
• maintenance therapy comprising vitamin D in doses equivalent to 800 – 2000 IU daily daily (occasionally up to 4,000 IU daily), given either daily or intermittently at higher doses.

Where correction of vitamin D deficiency is less urgent and when co-prescribing vitamin D supplements with an oral anti-resorptive agent, maintenance therapy may be started without the use of loading doses.

A month after a loading dose of vitamin D has been given, a calcium blood test is recommended to make sure a patient does not have primary hyperparathyroidism. This causes hypercalcaemia, which would be exacerbated by the high-dose vitamin D supplement.

Routine follow-up vitamin D blood tests are generally unnecessary unless vitamin D deficiency symptoms continue, a patient has malabsorption problems or it is likely they have not been taking the prescribed supplements. In some cases (for example before each intravenous (IV) zoledronate or denosumab dose) local Clinical Commissioning Group protocols may require vitamin D to be tested; check your local protocols for guidance relevant to your region.

The 'gold standard' for diagnosing osteoporosis is by measuring bone mineral density (BMD) using dual X-ray absorptiometry (DXA) and comparing the patient's result with that of a young adult of the same sex. In terms of SDs relative to the young adult normal, this is known as the T-score. BMD measurement is an important part of clinical decision-making and more information about the role of DXA scanning is given under 'How should GPs use bone densitometry?' on this page. Bone density, however, is not the only indicator for fracture risk and 25% of women suffering a hip fracture do not have a T-score in the osteoporotic range. Age, previous history of fragility fracture and family history are risk factors for future fractures, independent of BMD.

There are several fracture risk assessment tools, including FRAX® and QFracture, in the NICE short clinical guideline CG146 - Osteoporosis: Assessing the risk of fragility fracture, published in August 2012 and updated in 2017, and the QS149 - Osteoporosis Quality Standard published in 2017. Those at risk should be identified opportunistically, either because they have already suffered a fracture or because they have a clinical risk factor or disease associated with a low BMD. FRAX(r) is likely to overestimate fracture risk in patients who are already taking an osteoporosis treatment and fracture risk may be underestimated in patients with clinically apparent vertebral fracture, who have had multiple fragility fractures or where there has been high exposure to corticosteroids, alcohol or smoking. More information on the limitations of FRAX® is given by the International Society for Clinical Densitometry. As with any assessment tool or guidance, clinical judgement should always be used. The following table, taken from CG146, summarises the risk factors included in both tools (as of April 2012):

*e.g. type 1 diabetes, chronic hyperthyroidism, premature menopause, chronic liver disease, chronic malnutrition, chronic liver disease

Treatment thresholds have been proposed by the National Osteoporosis Guideline Group (NOGG) for use with the FRAX® calculated 10-year risks. These are based on fracture risks in the previous Royal College of Physicians guidelines. QFracture proposes thresholds based on the top 10% at highest risk:

• For women, the cut off for the top 10% at highest risk is 10-year risk of 11.1%
• For men, the cut off for the top 10% at highest risk is 2.6%

More information about the NOGG guideline is provided in the Initiation section of this ORPC.

Age, prior fracture and BMD are the most powerful predictors of future fracture risk. Consider a DXA scan in any patient with risk factors for osteoporosis in whom knowledge of BMD may influence management. Your local DXA service is likely to have locally agreed referral criteria to follow and there is also advice from bodies such as NICE (guidance on osteoporosis), SIGN (management of osteoporosis) and the Royal College of Physicians (corticosteroid guidance).

It may be helpful to use the FRAX® tool to estimate the patient's 10-year fracture probability and the associated NOGG guidance to decide whether DXA referral would be helpful. In Scotland, GPs should refer to the SIGN guidance which recommends using QFracture or FRAX® as the fracture risk assessment tool and referral for DXA when the 10 year risk exceeds 10%. Even if the fracture risk is very high it is helpful to know BMD in order to assess how well the patient is likely to respond to drug therapy and as a baseline to monitor progress. In most cases, it is clinically appropriate and feasible to send a patient over the age of 75 years for a DXA scan. When following SIGN guidance, it is recommended that all people with a history of fragility fractures over the age of 50 should be offered DXA scanning to evaluate the need for antiosteoporosis therapy.

When referring a patient for a DXA scan, the ROS leaflet Scans and tests may be helpful.

Most DXA services provide information about the interpretation of the BMD result for an individual patient. If this is not available, it is important to remember that there are other risk factors for fracture that should also be taken into account when interpreting the BMD result. BMD of the femoral neck can be entered into the FRAX® probability assessment for a patient who has not already been treated for osteoporosis.

Good practice for reporting DXA scans is outlined in the ROS Practical Guide Reporting Dual Energy Absorbtiometry Scans in adult fracture risk assessment.

The decision as to whether and when to repeat a DXA scan will depend on the initial results and the individual patient's circumstances. Factors to take into account are whether the patient has risk factors for accelerated bone loss (such as corticosteroid therapy) or medical conditions or treatment predisposing the patient to bone loss (such as inflammatory disease, malabsorption, aromatase inhibitor therapy or recent menopause). It is rarely helpful to repeat DXA scans within two years. Repeat measurements should be guided by local service agreements and the advice given at the time of the baseline scan.

There is a lack of consensus on this issue. DXA scans are of limited value in assessing response to treatment and a treatment response can rarely be demonstrated in less than 2 years. This is because the changes in BMD in response to treatment are small and slow and similar in magnitude to the error of the DXA measurement. However, repeat measurement of BMD can provide positive reinforcement to encourage continued compliance with treatment and is helpful in identifying patients who are not responding adequately to treatment.

As well as a DXA scan, the following additional tests should be carried out routinely to exclude secondary causes of osteoporosis:

• History and physical examination
• Blood cell count, sedimentation rate or C-reactive protein, serum calcium, albumin, creatinine, phosphate, alkaline phosphatase, liver transaminases
• Thyroid function test

The GP should also be aware that the following diseases and drugs are associated with increase fracture risk (adapted from SIGN 142).

Diseases:

• Diabetes
• Inflammatory rheumatic diseases
• Inflammatory bowel disease and
• malabsorption
• Epilepsy in institutionalised patients
• Primary hyperparathyroidism and
• endocrine diseases
• Chronic liver disease
• Neurological diseases (including
• Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke)
• Moderate to severe chronic kidney disease
• Asthma

Drugs:

• Long-term antidepressants
• Anti-epileptics
• Aromatase inhibitors
• Long-term depot medroxyprogesterone acetate (DMPA)
• Gonadotropin-releasing hormone (GnRH) agonists (in men with prostate cancer)
• Proton pump inhibitors (PPIs)
• Oral glucocorticoids
• Thiazolidinediones/glitazones (TZDs)

Ask opportunistically - annually if possible - about the number and characteristics of any falls in older patients, especially those aged over 75 years.

Patients with a fragility fracture who present with a fall are at highest risk of subsequent falls and should undergo a falls risk assessment. Those at highest risk are those with two or more falls in the previous year or a single fall plus a disorder of gait and/or balance (such as a postural instability, a failed 'get up and go' test, regular use of a walking aid, a history of stroke or Parkinson's disease), and those with a fall resulting in injury (such as a fracture). These should be offered a falls service referral but many will decline and the GP may have to pragmatically address the obvious risk factors for falls noted in the initiation section of this website. Another group that should be offered specialist assessment are those with a falls associated with syncope or with loss of consciousness to exclude underlying cardiac or neurological causes.

The key components of falls risk assessment in general practice would include medication review, visual acuity, vitamin D status, cognitive function, exercise recommendations, environmental check, check for postural hypotension and mobility assessment e.g. timed 'get up and go' test.

For more information, refer to:

• NICE: Falls in older people quality standard (QS86)
  Public Health England Falls and fractures: consensus statement and resources pack

The average number of patients per GP Practice in the UK is 7,183 (according to the Health and Social Care Information Centre's General Practice Trends in the UK to 2015). Many of those patients will present to the GP with a potential risk factor for fragility fracture and/or osteoporosis.

NICE gives the following as being the groups of patients that GPs should target their risk assessment (taken from NICE Clinical Guidance CG146):

1.1 Consider assessment of fracture risk:

• In all women aged 65 years and over and all men aged 75 years and over
  
  
• in women aged under 65 years and men aged under 75 years in the presence of risk factors, for example:
  
  
  • previous fragility fracture
    
    
  • current use or frequent recent use of oral or systemic glucocorticoids
    
    
  • history of falls
    
    
  • family history of hip fracture
    
    
  • other causes of secondary osteoporosis[7]
    
    
  • low body mass index (BMI) (less than 18.5 kg/m2)
    
    
  • smoking
    
    
  • alcohol intake of more than 14 units per week for women and more than 21 units per week for men.

1.2 Do not routinely assess fracture risk in people aged under 50 years unless they have major risk factors (for example, current or frequent recent use of oral or systemic glucocorticoids, untreated premature menopause or previous fragility fracture), because they are unlikely to be at high risk.